Sickle cell anemia is a disease which potentially afflicts some 8% of Black people in the United States who have Sickle Cell Trait, and their offspring. By the present invention, organophosphonate compounds are used to treat patients suffering with sickle cell anemia and related hemoglobinopathies and attendant peripheral vascular diseases.
Sickle cell anemia is one type of hemoglobinopathy whose origin has been traced to genetic defects. Sickle cell anemia is characterized by the formation of abnormal hemoglobin (HbS) and its inclusion in the erythrocytes (red blood cells) of people afflicted with this disease. The normal (non-sickle cell) erythrocyte is oxygenated in the lungs and travels through ever-narrowing blood vessels to the microvasculture (capillary bed) where oxygen delivery to the tissues is carried out. When entering the microvasculature, the erythrocytes must be able to pass through capillary channels which are narrower than the erythrocyte cells, themselves. Accordingly, the erythrocytes must be deformable so that passage through the narrowest capillary openings can occur, prior to return of the erythrocytes to the heart. In sickle cell anemia, the erythrocytes lack the normal deformability of healthy red blood cells. Accordingly, patients afflicted with this disease suffer gradual attrition due to luminal occlusion of small vessels by sickle cell erythrocytes in various stages of reversible and irreversible deformation. In short, frank entrapment of the non-deformable, sickle-shaped erythrocytes in the microvasculature occurs.
The clinical aspects of children suffering with sickle cell disease include a marked increase of pneumonia, diarrhea, urinary tract infection, meningitis, massive sepsis, and osteomyelitis, as compared with the non-sickle cell population. As might be expected with a disease state involving the microvasculature, thrombotic crises occur with some regularity, and pain, swelling and tenderness of various afflicted appendages occasioned by poor circulation are common.
In the sickle cell, itself, it appears that the cell membrane has somehow been damaged and is stiff and less deformable than normal, healthy erythrocytes. Other than the recognition that sickle cell anemia is an inheritable, genetic disease, little else is known of its etiology. Some workers have suggested that sickle cell erythrocytes are excessively permeable to calcium and that, somehow, the attachment of calcium to the endoface of the erythrocytes enhances their irreversible deformation characteristics.
Various organophosphonate compounds have recently been reported to be useful in the treatment of disease states involving anomalous mobilization and deposition of calcium phosphate salts, as occurs in osteoporosis and Paget's Disease (osteitis deformans). By the present invention, organophosphonate compounds are employed in the treatment of patients afflicted with sickle cell disease.
Quite surprisingly, moderate high levels of the organophosphonates in the blood do not appear to beneficially enhance the deformability of the sickle cell erythrocytes to the same extent as somewhat lower blood levels. Of course, the dose/response profiles of individual patients may vary somewhat. In any event, the present invention is based on the discovery that the organophosphonates restore the deformability of the sickled erythrocytes.